Acta Psychiatr Scand 2008: 118: 4–18 Copyright  2008 The Authors

All rights reserved Journal Compilation  2008 Blackwell Munksgaard

DOI: 10.1111/j.1600-0447.2008.01204.x ACTA PSYCHIATRICA
SCANDINAVICA

Review
Weight gain in bipolar disorder:
pharmacological treatment as a contributing
factor
Torrent C, Amann B, Sánchez-Moreno J, Colom F, Reinares M, C. Torrent1, B. Amann2,
Comes M, Rosa AR., Scott J, Vieta E. Weight gain in bipolar disorder: J. Snchez-Moreno1, F. Colom1,
pharmacological treatment as a contributing factor. M. Reinares1, M. Comes1,
A. R. Rosa1, J. Scott3, E. Vieta1
Objective: The aim of this paper was to review the association of most 1
Bipolar Disorders Program, Clinical Institute of
commonly used psychopharmacological drugs with weight gain in Neuroscience, University Hospital Clinic, University of
bipolar disorder. Barcelona, IDIBAPS, CIBER-SAM, Barcelona, Spain,
Method: Information was retrieved from a PubMed ⁄ Medline 2
Hospital Benito Menni, C.A.S.M., CIBER-SAM, Sant Boi
literature search reviewing weight gain in pharmacological studies in de Llobregat, Barcelona, Spain and 3University
bipolar disorder. Department of Psychiatry, Leazes Wing, Royal Victoria
Results: Obesity and overweight in bipolar disorder are partly related Infirmary, Newcastle upon Tyne, UK
to prescribed drugs with a strong effect of clozapine and olanzapine.
Lesser but still relevant weight gain is caused by quetiapine,
risperidone, lithium, valproate, gabapentin and by some
antidepressants. Ziprasidone, aripiprazole, carbamazepine and Key words: weight gain; pharmacological treatment;
lamotrigine do not seem to cause significant overweight. bipolar disorder
Conclusion: Careful monitoring of weight changes in patients before Eduard Vieta, MD, PhD, Clinical Institute of Neurosci-
and after drug prescription should be implemented in the clinical ence, University Hospital Clinic of Barcelona, IDIBAPS,
routine and drugs which potentially cause weight gain should be CIBER-SAM, Villarroel 170, 08036 Barcelona, Spain.
avoided in overweight patients with bipolar disorder. Furthermore, E-mail: evieta@clinic.ub.es
eating habits and daily activities should be targeted as they may also
have a significant impact on overall health and weight-related issues. Accepted for publication April 11, 2008

Summations
• Patients with bipolar disorder appear to have a higher risk of weight gain and obesity than the
general population.
• Weight gain and associated health problems in bipolar disorder may be partly related to drug
therapy. The weight gain liability of drugs used to treat bipolar disorder may range from none to very
high.
• Patients who develop this side-effect may discontinue therapy with more relapses and a possible
worse outcome. Potential side-effects should be discussed in advance.

Considerations
• We also included in our review process uncontrolled studies and data deriving from epilepsy studies.
• In most studies combination treatment strategies were applied which might have altered effects on
weight of individual drugs.
• We focused in our main objective on drugs causing weight gain, but other aspects such as eating
habits, daily activities, comorbidities and subthreshold symptoms may also have a significant impact
on overall health and weight-related issues.

4
 Weight gain and treatment of bipolar disorder

with serious mental illness have an increased

Introduction
prevalence of the metabolic syndrome. The study
Obesity occurs frequently in patients with certain by Heiskanen et al. (15) seem to indicate that a
mental disorders, and may be particularly relevant significant part of the risk of metabolic syndrome is
in schizophrenia, binge eating disorder and bipolar inherent in the psychiatric disease process itself and
disorder (1–3), which is characterized by recurrent that antipsychotic medication may be an indirect
episodes of depression and ⁄ or hypomania ⁄ mania factor in contributing to metabolic syndrome risk.
interspersed with periods of apparent remission. Weight gain and obesity are not only associated
The first controlled study of premorbid weight of with an increased mortality risk caused by coro-
32 patients with bipolar disorder was found to be nary diseases, type II diabetes, cancer, respiratory
within normal limits, suggesting that weight gain is problems, higher risk of infertility and arthrosis
probably related to illness and treatment variables (16–19), but also with psychological consequences,
(4). As a matter of fact, bipolar disorder in such as impaired self-image, low self-esteem and
particular is highly correlated with overweight reduced social interactions. However, little is
and obesity ranging from 20% to 35% exceeding known about the mechanisms involved in the
the prevalence in the general population (5–7). In a onset and maintenance of obesity in general.
controlled study on obesity and bipolar disorder, Some neurobiological findings have been found
the whole body and abdominal obesity was signif- to underlie obesity such as a dysfunction of
icantly more prevalent in 89 patients with euthymic neurotransmitter and of neuropeptide systems
bipolar in comparison with healthy subjects (2, 8). (20). In the past decade, a series of studies has
Of the 171 patients diagnosed by the Bipolar shown that coronary heart disease, hypercholes-
Disorder Center for Pennsylvanians, 49% had terolemia, hypertension, stroke and non-insulin
abdominal obesity and 30% metabolic syndrome dependency have the origins in foetal life (21). An
(9). association between low birth weight and the
Clinical findings most commonly associated with development of adult medical and metabolic dis-
metabolic syndrome include insulin resistance, eases was repeatedly demonstrated. The hypothesis
dyslipidemia, central obesity, hypertension, derives from the concept that exposure of the
impaired glucose tolerance and high rates of foetus to an adverse event in utero leads to a
artherosclerotic disease (10). Several definitions permanent programming of tissue function and
and criteria have been proposed for the metabolic subsequent increased risk of developing cardiovas-
syndrome associated with insulin resistance. The cular and metabolic diseases (22). Recent evidence
two most widely used definitions come from the suggested that hypothalamic–pituitary–adrenal
World Health Organization (WHO) and the US (HPA) axis dysregulation may play a significant
National Cholesterol Education Program (NCEP). role in the development of various components of
The definition proposed by the WHO diabetes the metabolic syndrome (23): the common patho-
group in 1998 (11) includes the following criteria: physiologic link between obesity, diabetes, mood
insulin resistance or its surrogates, impaired disorders and metabolic syndrome may be hyper-
glucose tolerance or diabetes, as essential compo- cortisolemia (10, 24).
nents, together with at least two of: raised blood Over the last 30 years, weight gain has also been
pressure, hypertriglyceridemia and ⁄ or low HDL increasingly recognized as an adverse effect of
cholesterol, obesity and microalbuminuria. The many psychopharmacological agents used in the
approach from the NCEP in 2001 (12) requires the treatment of affective disorders and schizophrenia.
presence of any three of these five components: So far, this phenomenon has been basically ignored
central obesity, raised blood pressure, raised in clinical evaluation. According to a recent study,
triglycerides, low HDL cholesterol and fasting only 20% of questioned psychiatrists do monitor
hyperglycemia. According to NCEP, metabolic waist circumference in their clinical practice (25).
syndrome is a precursor to, but does not include, As weight gain caused by medication may occur in
type 2 diabetes mellitus, whereas the WHO criteria a relatively short period of time, patients develop a
consider metabolic syndrome and diabetes to be negative view of their pharmacological treatment,
overlapping diagnostic categories. There are dif- which may have an unfavorable impact on their
ferent opinions between whether the metabolic treatment adherence and consequently on the
syndrome should be defined to mainly indicate course of their illness.
insulin resistance, the metabolic consequences of But how does medication cause onset and
obesity, risk of cardiovascular disease or simply a maintenance of weight gain ⁄ obesity in patients
collection of statistically related factors (13, 14). with bipolar disorder? On the one hand, anticho-
Several recent studies looked at whether patients linergic effects of some of the atypical antipsychotics

5
Torrent et al.

may lead to dryness of the mouth, stimulating some studies of anticonvulsants performed in
liquid intake and eventually greater consumption patients with epilepsy, keeping in mind that dos-
of caloric drinks. On the other hand, some med- ages used in epilepsy are sometimes higher and
ications stimulate appetite directly and might therefore might cause potentially more weight gain.
provoke comorbid binge eating. Some studies
suggest a positive correlation between the body
mass index (BMI) and the number of prescribed Results
drugs and the type of medication, hereby mainly
Weight gain and psychopharmacological agents
antipsychotics (2, 5). Some risk factors have been
identified to be correlated with weight gain during Bipolar disorder is a complex disorder, which is
pharmacotherapy: female gender, low pretreat- currently treated with a wide range of psychophar-
ment BMI, weight fluctuations during the adult- macological agents, such as lithium, anticonvul-
hood or premorbid or family history of obesity sants, antidepressants, typical and atypical
(26). However, a recent study proposes that normal antipsychotics. Various mechanisms of weight
weight and overweight patients are at greater risk gain related to psychotropic medication have
of medication-induced weight gain than obese been reported: i) lowering of the basal metabolic
patients (7). rate during depression with a reduction in spent
Although weight-related effects of psychotropic energy; ii) increase in leptin; iii) hyperprolactin-
medications may account for weight gain in some emia; iv) fluid retention; and v) change in insulin
individuals, other variables exist that influence the activity. Furthermore, the blockage of H1 hista-
onset and maintenance of obesity in bipolar mine-, 5-HT2C serotoninergic- and the D2 dopa-
disorder, such as atypical depression, eating minergic receptors is also the focus of research in
habits and behavior and physical inactivity (27). this aspect (29). Genetic variation partly deter-
A high percentage of patients with bipolar disorder mines also the degree of weight gain that occurs
for instance suffer from disturbed eating habits with antipsychotic drugs. Genetic polymorphisms
which do not meet the diagnostic criteria of a of the promoter region of the 5-HT2C receptor
specific eating disorder (28). have been associated with weight gain, noted for
example with chlorpromazine and risperidone (30).
The most important drugs used in bipolar disorder
Aims of the study
and their possible impact on weight changes are
The aim of this review was to critically highlight discussed in the following sections and are high-
the impact on weight gain of the most important lighted schematically in Table 1.
and commonly used drugs in bipolar disorder,
including lithium, anticonvulsants, antipsychotics
Lithium
and antidepressants, also focusing briefly on
potential mechanisms of action inducing this Lithium is widely used in unipolar depression,
undesirable side-effect. cyclothymia, acute euphoric mania and in the long-
term course of bipolar disorder. The main side-
effects of lithium are polydipsia, polyuria, cognitive
Material and methods
dysfunction, tremor and weight gain (31, 32).
A PubMed ⁄ Medline database was searched for Weight gain is experienced by 25% of patients on
articles published between 1980 and 2006 using the lithium treatment (33), which is in line with a study
keywords Ôweight gainÕ, Ômetabolic syndromeÕ, suggesting that over 30% of the patients treated
Ôbipolar disorderÕ, ÔlithiumÕ, ÔvalproateÕ, Ôcarbamaz- with lithium were suffering from obesity, repre-
epineÕ, ÔgabapentinÕ, ÔlamotrigineÕ, ÔantipsychoticsÕ, senting a higher rate than in the general population
ÔclozapineÕ, ÔolanzapineÕ, ÔrisperidoneÕ, Ôziprasi- (34). It is worth mentioning that a 7-year follow-up
doneÕ, ÔaripiprazoleÕ, ÔamisulprideÕ, Ôantidepres- study of patients on prophylactic lithium treatment
santsÕ. All clinical trials that stated information found that their body weight during the first
about the mean weight gain or the incidence of 1–2 years of lithium treatment increased and then
weight gain were eligible for inclusion in this remained constant (35).
review. A total of 206 studies were identified, of Weight gain linked to lithium is estimated to
whom finally 41 were included in this review. One range between 4.5 and 12 kg, explained by fluid
hundred and sixty-five articles were excluded retention, increased appetite or a lithium-related
because no numerical data about the weight subclinical hypothyroidism (36–39). Interestingly,
change were provided or simply were not designed weight gain related to lithium during the first year
as clinical trials. We also included in our review of treatment was found to be a predictor of

6
 Table 1. Summary of studies reporting weight outcomes in patients with bipolar disorders

Incidence of weight
Authors Population Drug Duration Dose Mean weight gain (kg) gain (%)* Comparator Significance (P)

Calabrese et al. (74) Recently depressed patients; n = 966 Li 18 months Li (0.8–1.1 mEq ⁄ l) Li: +1.2 PBO: 6 LTG, PBO <0.01 (LTG vs. Li)
in the open label; LTG (50, 200 or 400 mg ⁄ day) LTG: +4.2 Li: 10 comparison with PBO
n = 463 random assigned PBO: )2.2 LTG: 7 were not significant)
Henry et al. (40) Men (n = 22) Women (n = 38) taking Li 12 months 0.7 mmol ⁄ l NR Women: 47 Baseline <0.05
Li for at least 1 year, were Men: 4
interviewed about the side-effects
Bowden et al. (76) Obese (n = 155) and non-obese patients Li 18 months Obese: Li (838.8 mg ⁄ day) Obese: LTG )4.2, Li +6.1 NR LTG, PBO <0.05
(n = 399) and LTG (245.3 mg ⁄ day) and )0.6 with PBO
Non-obese: Li (844.2 mg ⁄ day) Non-obese: LTG )0.5,
and LTG (282.6 mg ⁄ day) Li +1.1 and +0.7 with PBO
Bowden et al. (104) Patients initially hospitalized for a Quetiapine 12 weeks Quetiapine (800 mg ⁄ day) Quetiapine + 2.6 (LOCF) Quetiapine: 1.9 Li, PBO <0.001 in the lithium
manic episode Li (0.6 and 1.4 mEq ⁄ l) and +3.3 (observed cases) PBO: 1 group
n = 302 patients randomized; PBO )0.008 (LOCF) +0.3 Li: 6.1 NS from PBO
quetiapine (n = 107); PBO (n = 97) and Li (observed cases)
(n = 98) Lithium +0.7 (LOCF) and +1
(observed cases)
Bowden et al. (50) Patients who met the recovery VPA 52 weeks VPA (0.6–156 lg ⁄ ml) and NR VPA: 21 Li, PBO VPA ‡ PBO (P = 0.004)
criteria within 3 months of the Li (0.1–2.7 mEq ⁄ l) Li: 13
onset of an index manic episode were PBO: 7
randomized to maintenance
treatment. VPA (n = 187); Li (n = 94); PBO
(n = 94)
Bowden et al. (73) Recently manic or hypomanic patients, LTG 18 months LTG (100–400 mg ⁄ day) NR LTG: 11 Li, PBO NR
open-label phase (n = 349), Li (0.8–1.1 mEq ⁄ l) Li: 10
double-blind; lamotrigine (n = 59), Li PBO: 2
(n = 46), PBO (n = 70)
Tohen et al. (143) VPA (n = 126) OLZ 47 weeks OLZ: 5–20 mg ⁄ day OLZ: +2.7 OLZ: 23.6 VPA <0.001
OLZ (n = 125) VPA: 500–2500 mg ⁄ day VPA: +1.2 VPA: 17.9
Coxhead et al. (144) Li (n = 16) Li 12 months NR Li: +4 NR CBZ NR
CBZ (n = 15) CBZ: )3.1
Ketter et al. (63) 92 BP patients CBZ-ERC 6 months Final dose 938 mg ⁄ day +0.7 NR PBO NR
Salloum et al. (145) 59 BP-I patients with alcoholism VPA 24 weeks 50–100 lg ⁄ ml NR PBO: 23.8 PBO 0.25
VPA: 14.3
Delbello et al. (105) Pediatric BP-I patients (n = 50) with Quetiapine 4 weeks 412 € 83 Quetiapine: 4.4 € 5.0 NR VPA 0.2
a manic or mixed episode VPA: 3.6 € 6.0
Vieta et al. (146) n = 26 OLZ + TPM 12 months OLZ: 9.9 € 4.8 mg ⁄ day )0.5 € 1.1 NR Baseline NS
TPM: 271.1 € 117.6 mg ⁄ day
Tohen et al. (147) Patients manic or mixed were OLZ 4 weeks 5–20 mg ⁄ day OLZ: +2.1 € 2.8 NA PBO 0.002
randomized to OLZ (n = 55) or PBO PBO: 0.45 € 2.3
(n = 60)
Tohen et al. (89) Patients (manic ⁄ mixed) not OLZ 6 weeks 5–20 mg ⁄ day NR VPA + OLZ: 35.3 VPA <0.005
responsive to more than 2 weeks Li + OLZ: 21.1 Li
to Li or VPA were randomized to VPA: 8.2
receive cotherapy with OLZ Li: 4.9
(n = 344)

7
Weight gain and treatment of bipolar disorder
8
Table 1. Continued

Incidence of weight
Authors Population Drug Duration Dose Mean weight gain (kg) gain (%)* Comparator Significance (P)

Tohen et al. (79) Patients with bipolar depression OLZ, Fluoxetine 8 weeks OLZ: 5–20 mg ⁄ day NR OLZ: 17.3 PBO OLZ vs. PBO <0.001
Torrent et al.

assigned to receive PBO (n = 377), OFC: 6 ⁄ 25, 6 ⁄ 50, OFC group: 17.4 OFC vs. PBO > 0.99
OLZ (n = 370), OLZ + fluoxetine 12 ⁄ 50 mg ⁄ day PBO group: 2.7
(n = 86)
Tohen et al. (92) Patients achieving the remission OLZ, Li, VPA 18 months Li: 0.6–1.2 mmol Combination: +2 OLZ comb: 27 Li NA
after treatment with OLZ + Li or VPA: 50–125 lg ⁄ ml Monotherapy: )1.8 Li ⁄ VPA mono: 6 VPA
VPA received Li or VPA plus OLZ: 5–20 mg ⁄ day PBO
either OLZ or PBO (n = 99)
Tohen et al. (148) Comparison flexible dosing of OLZ OLZ 12 weeks OLZ (5–20 mg ⁄ day) OLZ: +2.82 NR Haloperidol <0.001
(n = 234) and haloperidol Haloperidol (3–15 mg ⁄ day) Haloperidol: +0.02
(n = 219)
Biederman et al. (99) Preschool-age children wih bipolar Risperidone 8 weeks Risperidone: 0.25–2 mg ⁄ day Risperidone: 2.2 € 0.4 Risperidone: 10.1 € 6.1 OLZ NS
disorder (n = 31) OLZ: 1.25–10 mg ⁄ day OLZ: 3.2 € 0.7 OLZ: 12.9 € 7.1
Brown et al. (93) BP-I patients, depressed OLZ + fluoxetine 7 weeks OFC: 6 ⁄ 25, 6 ⁄ 50, 12 ⁄ 25, NR OFC: 23.4 LMG 0.001
(n = 410) (OFC) 12 ⁄ 50 mg ⁄ day LMG: 0
LMG: up to 200 mg ⁄ day
Perlis et al. (98) BP-I with non-psychotic acute OLZ 3 weeks OLZ: 15–20 mg ⁄ day OLZ: +2.46 OLZ: 16.4 Risperidone 0.005
manic or mixed episodes treated Risperidone: 2–6 mg ⁄ day Risperidone: +1.6 Risperidone: 3.7
with OLZ (n = 165) or risperidone
(n = 164)
Guille et al. (100) BP-I patients (n = 42) Clozapine 12 weeks Risperidone: 1.7 € 0.9 mg ⁄ day OLZ: +7.2 € 6.2 NR OLZ, 0.03
OLZ: 11.7 € 6.2 mg ⁄ day Risperidone: +3.5 € 5 risperidone
Clozapine: 210 € 119.4 mg ⁄ day Clozapine: no statistical
power
Calabrese et al. (72) Out-patients with BP-I depression LMG 7 weeks LMG: 50 mg ⁄ day LMG (50 mg ⁄ day): )0.4 NR PBO NR
(n = 195) LMG: 200 mg ⁄ day LMG (200 mg ⁄ day): 0
PBO: +0.2
Calabrese et al. (149) Rapid-cycling bipolar I or II disorder LMG 26 weeks LMG: 100–200 mg ⁄ day LMG: +1.1 NR PBO NR
(n = 324) PBO: )0.3
Wang et al. (71) 23 out-patients BP-I or II GBP 12 weeks 1725 mg ⁄ day +0.9 € 3.1 NR Baseline NS
Chengappa et al. (38) 214 patients: 123 man and 91 Li, VPA, TPM 12 months NR Li: +6.3 NR NR <0.001
women VPA: +6.4
TPM: )1.2
Weisler et al. (150) 204 patients manic or mixed, ERC-CBZ 3 weeks 400–1600 mg ⁄ day ERC-CBZ: +1.1 None PBO NA
n = 101 treated with ERC-CBZ and PBO: )0.1
n = 103 with placebo
Keck et al. (109) 76 bipolar patients recently Aripirazole 26 weeks 15 or 30 mg ⁄ day Aripiprazole: 1.7 € 0.8 Aripiprazole: 13 PBO 0.02
hospitalized and treated for a manic PBO: 0.5 € 0.8 PBO: 0
or mixed episode
DelBello et al. (151) Pediatric patients (n = 15) Quetiapine 6 weeks Quetiapine: 432 mg ⁄ day Quetiapine: 4.2 € 3.2 NR VPA NS
VPA: 104 g ⁄ ml VPA: 2.5 € 2.1
DelBello et al. (105) Pediatric patients in mood-stabilizer VPA 4 weeks 101 g ⁄ ml VPA: 3.6 € 6.0 NR Quetiapine NS
monotherapy (n = 40) Quetiapine: 4.4 € 5.0
Wagner et al. (152) Pediatric patients (n = 55) OXC 7 weeks 1515 mg ⁄ day OXC: +0.83 NR PBO 0.025
PBO: )0.13
 Table 1. Continued

Incidence of weight
Authors Population Drug Duration Dose Mean weight gain (kg) gain (%)* Comparator Significance (P)

DelBello et al. (153) Pediatric patients (n = 29) TOP 4 weeks 278 € 121 mg ⁄ day TOP: )1.8 € 2.0 TOP: )2.7 PBO <0.001
PBO: 0.9 € 1.4 PBO: 1.4
Frankenburg et al. (154) n = 30 women with bipolar disorder VPA 6 months 50–100 mg ⁄ l VPA: 1.1 € 2.5 VPA: 1.9 € 3.9 PBO NS
comorbid with borderline personality PBO: 0.1 € 1.8 PBO: 0.1 € 3.1
Bowden et al. (155) n = 377 with a manic episode VPA-ER 21 days 3057 mg VPA-ER: 1.8 VPA-ER: 9 PBO 0.036
PBO: 0.5 PBO: 3
Zajecka et al. (91) 120 BP-I patients hospitalized VPA 12 weeks VPA: 2115 mg ⁄ day VPA: 2.5 NR OLZ OLZ > VPA 0.049
with acute mania OLZ: 14.7 mg ⁄ day OLZ: 4
Khanna et al. (96) 290 BP patients with a current Risperidone 3 weeks 1–6 mg ⁄ day Risperidone: 0.06 NR PBO NR
manic or mixed episode PBO: 0.07
Yatham et al. (101) Patients taking mood-stabilizer Li, CBZ, VPA 3 weeks Risperidone: 4 mg ⁄ day Risperidone: 1.7 NR Risperidone, 0.012
with acute mania were PBO: 0.5 PBO
randomized with risperidone
(n = 75) or PBO (n = 76)
Vieta et al. (156) 58 BP-I manic patients Risperidone, 12 months Risperidone: 2.7 € 1.7 mg ⁄ day )1.1 € 0.4 NR Baseline NR
TPM TPM: 236.3 € 138.1 mg ⁄ day
Vieta et al. (157) n = 347 Aripirazole 12 weeks Aripirazole: 15 mg ⁄ day Aripirazole: +0.27 NR Haloperidol NS
Haloperidol: 10 mg ⁄ day Haloperidol: )0.10
Vieta et al. (158) 20 manic patients Amisulpride 6 weeks 680 mg ⁄ day 0.4 € 0.9 NR Baseline NS
Tohen et al. (88) 431 BP patients (manic ⁄ mixed) OLZ 52 weeks OLZ: 13.5 mg ⁄ day OLZ: 1.8 NR Li <0.001
Li: 1003.3 mg ⁄ day Li: )1.4
Silverstone (159) 156 patients with bipolar depression MCB 8 weeks MCB: 450–750 mg ⁄ day NR MCB: 1.2 IMI NR
IMI: 150–250 mg ⁄ day IMI: 0.1

* >5–7% from baseline. NR, not reported; NS, not significant; LTG, lamotrigine; PBO, placebo; Li, lithium; VPA, valproic acid; CBZ, carbamazepine; CBZ-ERC, extended-release carbamazepine; BP, bipolar disorder; OFC, olanzapine–fluoxetine
combination; TPM, topiramate; comb, combination; mono, monotherapy; LTG, lamotrigine; GBP, gabapentine; MCB, moclobemide; IMI, imipramine.

9
Weight gain and treatment of bipolar disorder
Torrent et al.

developing later a subclinical hypothyroidism, with and 10 kg over a period of 3–12 months, but may
more women than men being at risk of this be up to 20 kg, depending on the duration of the
particular side-effect (40). Another study suggested intake (56). Another potential side-effect of VPA,
that thyroid dysfunction is very frequent in ovarian polycystic syndrome, may also contribute
patients with bipolar disorder on lithium treatment to weight gain (57).
and proposed therefore a slower response to acute
treatment and worse long-term outcome in these
Carbamazepine
patients (41).
Another reason for weight gain is that lithium Carbamazepine (CBZ) is another anticonvulsant
might lower the metabolic rate and increase food drug used as mood stabilizer in the treatment of
intake secondary to an improvement of mood. The bipolar disorder. A significant amount of data is
hormone leptin is also suggested to be associated available which confirms its efficacy in mania (58)
with lithium-induced weight gain (42). An under- and prophylaxis, although it is not generally
estimated, but potentially relevant, factor is poly- recommended as first-line treatment (59). Studies
dipsia, as some patients may start drinking large show controversial results with respect to CBZ-
amounts of high-caloric drinks. associated weight gain (60). In a randomized,
In general, increase in weight due to lithium double-blind study investigating weight effects of
appears to be dose dependent, with increases in adjunctive therapy with CBZ (n = 64) or tiagabine
weight less likely at plasma lithium levels below (n = 64) in patients taking phenytoin for partial
0.8 mmol ⁄ l (43). An increase in weight may have a seizures, patients gained 2.62 kg after 16 weeks on
pronounced negative impact on adherence, even in CBZ, but lost 0.88 kg on tiagabine (61). Corman
patients experiencing an amelioration of their et al. (62) found that nearly half of the patients
affective symptoms (43). Weight gain in patients receiving CBZ gained weight, which is in contrast
on lithium as prophylactic treatment was consid- to a 6-month open-label study in bipolar disorder,
ered to be related to poor adherence in up to 50% where no significant weight gain was noted (63).
of cases, increasing to 90% of patients having Potential mechanisms for CBZ-induced weight
seriously considered discontinuing treatment (33, gain have been discussed, such as appetite stimu-
44). Although in many cases non-adherence comes lation, fluid retention, changes in lipid profile and
as a result of several factors, including not only edema, but hyperglycemia does not occur. Keeping
side-effects but often poor illness awareness (45– in mind the paucity of controlled long-term data of
47), a sudden discontinuation of lithium treatment CBZ, weight gain in bipolar disorder seems
is highly associated with relapse, worsening the unlikely, even though some increase in weight
course of the illness and increasing suicidality (48). was noted in some epilepsy studies (64). In a
randomized double-blind study of patients with
treatment-naive bipolar disorder, only increased
Valproate
appetite occurred more often with CBZ than with
The anticonvulsant valproate (VPA) has been lithium (33% vs. 17% respectively), weight was not
shown to be effective in the treatment of patients assessed (65).
with bipolar disorder with mania, mixed episodes
or substance abuse (49). Prophylactic data of VPA
Gabapentin
remain controversial so far (50, 51). The most
common side-effects are nausea, vomiting, tremor, Gabapentin (GBP) is indicated as an adjuvant
drowsiness and weight gain (38, 50). The latter is treatment for partial epileptic seizures. Clinical
also linked to an increasing rate of patients studies on the efficacy of GBP in bipolar disorder
discontinuing VPA (43, 52). The prevalence of are controversial. Some studies were negative and
weight gain with VPA is estimated to occur in did not show any efficacy as an antimanic agent
3–20% of patients treated with the substance (53). (66, 67), while other data suggest some mild effect
A double-blind, 1-year trial of VPA in bipolar on prevention of further affective episodes during
disorder indicated that approximately a quarter of long-term treatment (68). In epilepsy studies, GBP
patients suffered from weight gain compared with caused as much dose-dependent weight gain in
the control group (50). In a 5-year follow-up study monotherapy as it did as an add-on agent.
with epileptic patients, weight gain of 5.5 kg or Approximately 25% of patients gained more than
more was observed in 20% of VPA-treated patients 10% in weight compared with their initial body
(54). An open study found a mean weight gain of weight (69, 70). In patients with bipolar disorder,
21 kg over 7 years in 11 of 22 epileptic women (55). Wang et al. (71) reported a mean increase of 0.9–
Weight gain attributed to VPA ranges between 3 3 kg after 12 weeks of treatment.

10
 Weight gain and treatment of bipolar disorder

done (78). Its powerful antimanic effects and

Lamotrigine
limited weight gain liability have to be counterbal-
Lamotrigine (LTG), increasingly prescribed in anced by tolerability and safety issues, and its
depressed patients with bipolar disorder, is also limited value in the prevention of depressive
used as a prophylactic agent, especially in the episodes (79, 80).
prevention of depressive phases and rapid cycling
in bipolar disorder (72–74). LTG is generally well
Atypical antipsychotics
tolerated, particularly with respect to weight gain.
In a large, randomized 18-month study, patients Atypical antipsychotics, such as olanzapine, ris-
first received 200 mg LTG per day until they were peridone, quetiapine, ziprasidone and aripiprazole,
stabilized and afterwards assigned to LTG, lithium and to some extent clozapine and amisulpride, are
or placebo groups. At the end of the study, the frequently used to treat patients with bipolar
observed mean changes in body weight from disorders. Some of these compounds, especially
randomization were 1.2, 4.2 and )2.2 kg for olanzapine, are being used now in maintenance
placebo, lithium and LTG respectively. Incidence treatment, which makes the weight gain issue even
of patients with 7% or greater increase in body more relevant. The long-term trials available,
weight at the final double-blind study visit was 6%, though, often report weight gain after randomiza-
10% and 7% for the placebo, lithium and LTG tion, whereas the relevant figure is the addition of
groups respectively (74). In another trial, 182 out- weight gained during the acute, open phase and the
patients with rapid-cycling bipolar disorder were weight gained after randomization. Interestingly,
stabilized while on adjunctive LTG and then patients who were randomized to placebo or mood
randomized to LTG or placebo groups. The stabilizers in the olanzapine trials lost weight after
mean change in body weight from screening to discontinuation of olanzapine.
day 1 of randomization or premature withdrawal Retrospective studies have found increases in
was 0.3 kg. The mean weight for the LTG mono- weight between 9% and 11% in patients on
therapy completers remained unchanged. During clozapine treatment for more than 6 months com-
the randomized phase, the placebo monotherapy pared with their initial body weight (81). In
completers had a mean change of 1.1 kg. In another study with patients treated with 500 and
another study, depressed patients with bipolar I 600 mg of clozapine per day for more than
disorder received either placebo, LTG 50 or 90 months, almost half of the patients gained
200 mg ⁄ day as monotherapy for 7 weeks (72). 20% or more of their initial body weight (82).
The mean body weight at screening was Similar results were found in a randomized,
78.6 ± 16.0, 76.5 ± 17.6 and 82 ± 18.9 kg and double-blind study comparing clozapine and hal-
the mean change from screening to the end of the operidol. In this study, the patients treated with
study was 0.2, )0.4 and 0.0 kg respectively. clozapine for 10 weeks gained on average 7% of
Another recent study also confirmed that LTG is their initial body weight, whilst those who were
not associated with significant weight gain (75). randomized to haloperidol gained only 1%.
Moreover, LTG was found to reduce weight when Among the patients who chose to continue with
compared with lithium in a sample of obese clozapine, beyond the 10-week endpoint, 58% had
patients with bipolar I disorder (76). gained 10% of their pretreatment weight and 21%
gained more than 20% of their original weight (83).
Weight gain is also associated with olanzapine
Typical antipsychotics
(84–86). Olanzapine shows efficacy in treating
The prophylactic use of typical antipsychotics is patients with mania, bipolar depression (especially
uncommon and is generally not recommended when combined with fluoxetine) and in relapse
owing to the high prevalence of adverse effects prevention in patients with bipolar disorder
(77). Prolonged exposure to these medications (79, 87, 88). In a 4-week study comparing the
carries a higher risk of extrapyramidal side-effects efficacy and safety of olanzapine vs. placebo for the
and tardive dyskinesia. Among the conventional treatment of acute bipolar mania, olanzapine-
antipsychotics, molindone, loxapine and pimozide treated patients had a statistically significant
are associated with less weight gain, but are rarely greater mean weight gain (±SD) than placebo-
used in current clinical practice. Haloperidol, treated patients (2.1 ± 2.8 vs. 0.45 ± 2.3 kg
which is still widely used in some countries, while respectively) (87). In another 3-week study com-
in others has been less frequently prescribed due to paring olanzapine and divalproex for treatment of
undesirable side-effects, is significantly less associ- mania, the average weight gain with olanzapine
ated with weight gain than olanzapine and risperi- treatment was 2.5 kg compared with 0.9 kg with

11
Torrent et al.

divalproex treatment (89). These findings were Weight gain also seems to be associated with
confirmed in a double-blind 12-week randomized quetiapine, which is increasingly used in mania,
clinical trial where general adverse events, includ- bipolar depression and in the prevention of affec-
ing weight gain, were reported to be more frequent tive episodes (102). An increase of 7% in initial
in olanzapine compared with divalproex-treated body weight in 25% of the patients was reported in
patients (25% vs. 10%) (90). Accordingly, Zajecka schizophrenia (103). A double-blind, 12-week
et al. (91) found no significant difference regarding study comparing lithium, quetiapine and placebo
efficacy in olanzapine and divalproex groups, but groups in mania suggested a significantly higher
the latter was associated with a more favorable mean weight gain in the quetiapine group than in
adverse event profile and significantly less weight the placebo group: 2.6 vs. )0.08 kg using LOCF or
gain than olanzapine group. Comparing combina- and 3.3 vs. 0.3 kg in observed cases (104). Most
tion therapy and monotherapy in a study with patients who gained ‡7% of their weight belonged
patients treated with either lithium or VPA plus to the group with BMI <25 (underweight or
either olanzapine or placebo, weight gain was more normal weight). In a randomized pilot study,
common in the combination therapy than in comparing quetiapine and divalproex for adoles-
monotherapy (20% vs. 6%). Loss of weight in cent mania did not reveal a statistically significant
the monotherapy patients was probably secondary difference between the groups in weight gain (105).
to the discontinuation of olanzapine (92). The potential for weight gain in ziprasidone
Depressed patients with bipolar I disorder were treatment is less than that of chlorpromazine,
treated with the combination of olanzapine and clozapine and olanzapine treatments or even does
fluoxetine or LTG monotherapy, and they not occur (106). There is a considerable difference
showed more weight gain in the combination between the weight gained by patients taking
group (93). ziprasidone and those treated with olanzapine.
In a 3-week randomized, controlled trial, After 1 year of treatment, virtually no weight
adjunctive risperidone therapy for mania was change is observed in patients on ziprasidone
associated with significant weight gain as well treatment, in contrast to patients on olanzapine
(2.5 kg; SD 7) (94). This is in line with a random- treatment who gained up to 12 kg (1).
ized, double-blind trial comparing haloperidol and Aripiprazole appears to be associated with lim-
risperidone in the treatment of acute mania with a ited weight gain. In a meta-analysis by Marder
mean increase in weight at the 12-week endpoint of et al. (107), schizophrenic patients in the aripip-
1.4 ± 4.6 kg in the risperidone group and razole group showed a significant, but minimal
0.8 ± 3.5 kg in the haloperidol group (95). How- mean increase in body weight from baseline
ever, when looking into drug-induced weight gain, (<1 kg) compared with placebo. In a placebo-
it is also relevant to consider the geographical and controlled, double-blind study of aripiprazole in
ethnic environment. Hence, in a 3-week placebo- acute manic patients, both groups experienced a
controlled trial in patients with mania from India, slight decrease in mean body weight from baseline
weight gain was comparable in the risperidone to endpoint (placebo: )0.8 kg and aripiprazole:
and placebo groups: 0.07 kg in the placebo group )0.3 kg) (108). In a 6-month placebo-controlled
and 0.06 kg in the risperidone group (96). More- trial, patients with bipolar disorder on aripiprazole
over, a 6-month prospective study of 21 patients gained 0.5 ± 0.8 kg (109).
on stable doses of risperidone and olanzapine
showed less weight gain with risperidone (97).
Antidepressants
Similar results were found in other studies com-
paring risperidone and olanzapine (98), including Antidepressants are the treatment of choice in
also an investigation of preschool children with unipolar depression, but their use in bipolar
bipolar disorder (99). Allison et al. (1) conducted disorders is controversial (110–113). Weight gain
a study that compared the effects of antipsychotics during depressive episodes and while on antide-
on body weight and found that the mean increase pressant treatment can have different causes, and it
in weight after 10 weeks of treatment was 4.45 kg can even be a sign of improvement in patients
for clozapine, 4.15 kg for olanzapine and 2.92 kg initially presenting with hyporexia and weight loss
for risperidone. Findings were similar in another as a feature of their depression. Alternatively, it
study comparing risperidone, olanzapine and might also be a residual symptom in patients, who
clozapine monotherapies (100). The mean increase show hyperphagia in atypical depression (114).
in weight in a 3-week randomized trial was Last but not the least, an increase in weight can
significantly higher in the risperidone group than also be considered as a iatrogenic effect of antide-
in the placebo group (101). pressant treatment. Various studies have been

12
 Weight gain and treatment of bipolar disorder

carried out with the aim to clarify this debate (115–

Discussion
117). The majority of the studies, however, attri-
bute weight gain during the acute and maintenance Researches are increasingly being undertaken to
phases directly to the pharmacological treatment, find the relationship between bipolar disorder and
which may increase appetite and craving for weight gain. Obesity and overweight are estab-
carbohydrates and sweets (118). Weight gain may lished risk factors for morbidity and mortality, as
also persist despite complete remission of depres- well as for having negative psychological conse-
sive symptoms, eventually leading to a negative quences. In addition, Fagiolini et al. (131) found
impact on long-term adherence (119). that obesity is correlated with a poorer outcome in
patients with bipolar I disorder, the number of
Tricyclics Amongst the antidepressants, tricyclics patients experiencing a depressive recurrence was
may increase appetite and promote carbohydrate higher in the obese than in the non-obese group.
craving, thus carrying a potential high risk of Being overweight is a multifactorial problem for
weight gain. Garland et al. (37) reported that patients with bipolar disorder, and is not only a
dose-related weight gain in patients on tricyclic consequence of prescribed medications. However,
antidepressant treatment ranged from 0.4 to this side-effect has to be taken into account: a
4.1 kg ⁄ month, depending on the duration of treat- pronounced effect might occur with clozapine,
ment. Amitryptiline and imipramine have been olanzapine, and to a lesser degree with quetiapine,
reported to induce the greatest weight gain (120), risperidone, lithium, VPA, GBP and some antide-
which is in contrast to results of a longitudinal pressants, such as amytryptiline imipramine, par-
study performed by Fernstrom (121). However, the oxetine and mirtazapine. By contrast, ziprasidone,
latter study did not include patients who might aripiprazole, CBZ, LTG, venlafaxine, other SSRIs
have discontinued treatment due to substantial or moclobemide are probably not related to cause
weight gain. much weight gain. However, in the majority of
these drugs, data regarding weight changes are
MAOIs Phenelzine, a monoamine oxidase inhibi- scarce, especially concerning prospective and con-
tor (MAOI), may also increase appetite and cause trolled studies, and conclusions have to be consid-
weight gain to an extent comparable with that of ered with caution. Moreover, there is substantial
imipramine (37), in contrast to moclobemide, a interpersonal variability in treatment response and
reversible MAOI, which does not appear to affect in weight gain liability; so, decisions have always to
body weight. In a comparative study, patients be taken on an individualized basis. However, in
treated with tricyclic antidepressants gained an light of the ongoing obesity epidemic in wealthy
average of 2 kg over 7 weeks, while weight changes countries, action is urgently needed, and the
were not seen in patients taking moclobemide mentally ill are a particularly vulnerable popula-
(122). The other more frequently used MAOI, tion who deserve extra care. This includes healthy
tranylcypromine, was not reported to cause weight eating habits, exercise, and of course a careful
gain owing to its appetite-suppressive effect (123). selection of treatments for their mental condition.
Bipolar disorder is generally treated with several
SSRIs The SSRIs are in general associated with medications (132, 133) and weight gain liability of
reduced appetite and a higher basal metabolic rate, particular drugs and their combination should be
which in some cases can cause weight loss, espe- considered in light of the findings described above.
cially during the acute phase (124). However, On the other hand, though, there is no health
paroxetine seems to be associated with weight without mental health, which means that weight
gain when treatment is started (124–126). During gain considerations should never take prominence
the maintenance phase, patients usually gain over treating effectively severe psychiatric symp-
weight, which has to be interpreted with caution. toms that may impair quality of life and pose the
This finding could be connected with treatment, patient at risk of suicide. Residual symptoms, for
but may also be due to regaining weight previously instance, may be a source of poor habits and
lost whilst being depressed. sedentarism which might be addressed by means of
more effective treatment (134).
Others Newer antidepressants, such as bupropion, Although most experts agree that obesity pre-
have been reported to be associated with weight vention ought to be given the highest priority, data
loss (127). Nefazodone and venlafaxine are also not and research in this area are also limited. However,
generally associated with any significant variations preliminary research indicates that patients with
in body weight (114, 128, 129), whilst mirtazapine is bipolar disorder with overweight or obesity benefit
associated with a significant weight gain (130). from psychological interventions, particularly

13
Torrent et al.

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